Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2019 Publisher: Ibigen S.r.l., Via Fossignano, 2, 04011 Aprilia (LT), Italy
Levofloxacin Ibigen solution for infusion must not be used:
Methicillin-resistant S. aureus are very likely to possess co-resistance to fluoroquinolones, including levofloxacin. Therefore levofloxacin is not recommended for the treatment of known or suspected MRSA infections unless laboratory results have confirmed susceptibility of the organism to levofloxacin (and commonly recommended antibacterial agents for the treatment of MRSA-infections are considered inappropriate).
Resistance to fluoroquinolones of E. coli – the most common pathogen involved in urinary tract infections – varies across the European Union. Prescribers are advised to take into account the local prevalence of resistance in E. coli to fluoroquinolones.
Inhalation Anthrax: use in humans is based on in vitro Bacillus anthracis susceptibility data and on animal experimental data together with limited human data. Treating physicians should refer to national and/or international consensus documents regarding the treatment of anthrax.
Epidemiologic studies report an increased risk of aortic aneurysm and dissection after intake of fluoroquinolones, particularly in the older population.
Therefore, fluoroquinolones should only be used after careful benefit-risk assessment and after consideration of other therapeutic options in patients with positive family history of aneurysm disease, or in patients diagnosed with pre-existing aortic aneurysm and/or aortic dissection, or in presence of other risk factors or conditions predisposing for aortic aneurysm and dissection (e.g. Marfan syndrome, vascular Ehlers-Danlos syndrome, Takayasu arteritis, giant cell arteritis, Behcet’s disease, hypertension, known atherosclerosis).
In case of sudden abdominal, chest or back pain, patients should be advised to immediately consult a physician in an emergency department.
The recommended infusion time of at least 30 minutes for 250 mg or 60 minutes for 500mg Levofloxacin Ibigen solution for infusion should be observed. It is known, for ofloxacin, that during infusion tachycardia and a temporary decrease in blood pressure may develop. In rare cases, as a consequence of a profound drop in blood pressure, circulatory collapse may occur. Should a conspicuous drop in blood pressure occur during infusion of levofloxacin, (l-isomer of ofloxacin) the infusion must be halted immediately.
Tendinitis may rarely occur. It most frequently involves the Achilles tendon and may lead to tendon rupture. Tendinitis and tendon rupture, sometimes bilateral, may occur within 48 hours of starting treatment with levofloxacin and have been reported up to several months after discontinuation of treatment. The risk of tendinitis and tendon rupture is increased in patients aged over 60 years, inpatients receiving daily doses of 1000 mg and in patients using corticosteroids. The daily dose should be adjusted in elderly patients based on creatinine clearance (see section 4.2). Close monitoring of these patients is therefore necessary if they are prescribed Levofloxacin Ibigen. All patients should consult their physician if they experience symptoms of tendinitis. If tendinitis is suspected, treatment with Levofloxacin Ibigen must be halted immediately, and appropriate treatment (e.g. immobilisation) must be initiated for the affected tendon (see sections 4.3 and 4.8).
Diarrhoea, particularly if severe, persistent and/or bloody, during or after treatment with levofloxacin, (including several weeks after treatment) may be symptomatic of Clostridium difficile-associated disease (CDAD). CDAD may range in severity from mild to life threatening, the most severe form of which is pseudomembranous colitis (see section 4.8). It is therefore important to consider this diagnosis in patients who develop serious diarrhoea during or after treatment with levofloxacin If CDAD is suspected or confirmed, levofloxacin should be stopped immediately and appropriate treatment initiated without delay. Anti-peristaltic medicinal products are contraindicated in this clinical situation.
Quinolones may lower the seizure threshold and may trigger seizures. Levofloxacin is contraindicated in patients with a history of epilepsy (see section 4.3) and, as with other quinolones, should be used with extreme caution in patients predisposed to seizures or concomitant treatment with active substances that lower the cerebral seizure threshold, such as theophylline (see section 4.5). In case of convulsive seizures (see section 4.8), treatment with levofloxacin should be discontinued.
Patients with latent or actual defects in glucose-6-phosphate dehydrogenase activity may be prone to haemolytic reactions, when treated with quinolone antibacterial agents Therefore, if levofloxacin has to be used in these patients, potential occurrence of haemolysis should be monitored.
Since levofloxacin is excreted mainly by the kidneys, the dose of Levofloxacin Ibigen should be adjusted in patients with renal impairment (see section 4.2).
Levofloxacin can cause serious, potentially fatal hypersensitivity reactions (e.g. angioedema up to anaphylactic shock), occasionally following the initial dose (see section 4.8). Patients should discontinue treatment immediately and contact their physician or an emergency physician, who will initiate appropriate emergency measures.
Cases of severe bullous skin reactions such as Stevens-Johnson syndrome or toxic epidermal necrolysis have been reported with levofloxacin (see section 4.8). Patients should be advised to contact their doctor immediately prior to continuing treatment if skin and/or mucosal reactions occur.
As with all quinolones, disturbances in blood glucose, including both hypoglycaemia and hyperglycaemia have been reported (see section 4.8), usually in diabetic patients receiving concomitant treatment with an oral hypoglycaemic agent (e.g. glibenclamide) or with insulin. Cases of hypoglycaemic coma have been reported. In diabetic patients, careful monitoring of blood glucose is recommended.
Photosensitisation has been reported with levofloxacin (see section 4.8). It is recommended that patients should not expose themselves unnecessarily to strong sunlight or to artificial UV rays (e.g. sunray lamp, solarium), during treatment and for 48 hours following treatment discontinuation in order to prevent photosensitisation.
Due to possible increase in coagulation tests (PT/INR) and/or bleeding in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g. warfarin), coagulation tests should be monitored when these drugs are given concomitantly (see section 4.5).
Psychotic reactions have been reported in patients receiving quinolones, including levofloxacin. In very rare cases these have progressed to suicidal thoughts and self-endangering behaviour sometimes after only a single dose of levofloxacin (see section 4.8). In the event that the patient develops these reactions, levofloxacin should be discontinued and appropriate measures instituted. Caution is recommended if levofloxacin is to be used in psychotic patients or in patients with history of psychiatric disease.
Caution should be taken when using fluoroquinolones, including levofloxacin, in patients with known risk factors for prolongation of the QT interval such as, for example:
Elderly patients and women may be more sensitive to QTc-prolonging medications. Therefore, caution should be taken when using fluoroquinolones, including levofloxacin, in these populations.
(See section 4.2 Elderly, 4.5, 4.8, 4.9).
Peripheral sensory neuropathy and peripheral sensory motor neuropathy have been reported in patients receiving fluoroquinolones, including levofloxacin, which can be rapid in its onset (see section 4.8). Levofloxacin should be discontinued if the patient experiences symptoms of neuropathy in order to prevent the development of an irreversible condition.
Cases of hepatic necrosis up to fatal hepatic failure have been reported with levofloxacin, primarily in patients with severe underlying diseases, e.g. sepsis (see section 4.8). Patients should be advised to stop treatment and contact their doctor if signs and symptoms of hepatic disease develop such as anorexia, jaundice, dark urine, pruritus or tender abdomen.
Fluoroquinolones, including levofloxacin, have neuromuscular blocking activity and may exacerbate muscle weakness in patients with myasthenia gravis. Post marketing serious adverse reactions, including deaths and the requirement for respiratory support, have been associated with fluoroquinolone use in patients with myasthenia gravis. Levofloxacin is not recommended in patients with a known history of myasthenia gravis.
If vision becomes impaired or any effects on the eyes are experienced, an eye specialist should be consulted immediately (see sections 4.7 and 4.8).
The use of levofloxacin, especially if prolonged, may result in overgrowth of non-susceptible organisms. If superinfection occurs during therapy, appropriate measures should be taken.
In patients treated with levofloxacin, determination of opiates in urine may give false-positive results. It may be necessary to confirm positive opiate screens by more specific method.
Levofloxacin may inhibit the growth of Mycobacterium tuberculosis and, therefore, may give false-negative results in the bacteriological diagnosis of tuberculosis.
This medicinal product contains 177 mg sodium per 50 ml and 354 mg per 100 ml, equivalent to 8.85% and 17.7% respectively of the WHO recommended maximum daily intake of 2g sodium for an adult.
No pharmacokinetic interactions of levofloxacin were found with theophylline in a clinical study. However a pronounced lowering of the cerebral seizure threshold may occur when quinolones are given concurrently with theophylline, non-steroidal anti-inflammatory drugs, or other agents which lower the seizure threshold.
Levofloxacin concentrations were about 13% higher in the presence of fenbufen than when administered alone.
Probenecid and cimetidine had a statistically significant effect on the elimination of levofloxacin. The renal clearance of levofloxacin was reduced by cimetidine (24%) and probenecid (34%). This is because both drugs are capable of blocking the renal tubular secretion of levofloxacin. However, at the tested doses in the study, the statistically significant kinetic differences are unlikely to be of clinical relevance.
Caution should be exercised when levofloxacin is coadministered with drugs that affect the tubular renal secretion such as probenecid and cimetidine, especially in renally impaired patients.
Clinical pharmacology studies have shown that the pharmacokinetics of levofloxacin were not affected to any clinically relevant extent when levofloxacin was administered together with the following drugs: calcium carbonate, digoxin, glibenclamide, ranitidine.
The half-life of ciclosporin was increased by 33% when coadministered with levofloxacin.
Increased coagulation tests (PT/INR) and/or bleeding, which may be severe, have been reported in patients treated with levofloxacin in combination with a vitamin K antagonist (e.g. warfarin). Coagulation tests, therefore, should be monitored in patients treated with vitamin K antagonists (see section 4.4).
Levofloxacin, like other fluoroquinolones, should be used with caution in patients receiving drugs known to prolong the QT interval (e.g. Class IA and III anti-arrhythmics, tricyclic antidepressants, macrolides, antipsychotics). (See section 4.4 QT interval prolongation).
In a pharmacokinetic interaction study, levofloxacin did not affect the pharmacokinetics of theophylline (which is a probe substrate for CYP1A2), indicating that levofloxacin is not a CYP1A2 inhibitor.
There are limited amount of data from the use of levofloxacin in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). However in the absence of human data and due to that experimental data suggest a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, Levofloxacin Ibigen must not be used in pregnant women (see sections 4.3 and 5.3).
Levofloxacin Ibigen is contraindicated in breast-feeding women. There is insufficient information on the excretion of levofloxacin in human milk; however other fluoroquinolones are excreted in breast milk. In the absence of human data and due to that experimental data suggest a risk of damage by fluoroquinolones to the weight-bearing cartilage of the growing organism, levofloxacin must not be used in breast-feeding women (see sections 4.3 and 5.3).
Levofloxacin caused no impairment of fertility or reproductive performance in rats.
Levofloxacin Ibigen has some undesirable effects (e.g. dizziness/vertigo, drowsiness, visual disturbances) which may impair the patient’s ability to concentrate and react, and therefore may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).
The information given below is based on data from clinical studies in more than 8300 patients and on extensive post marketing experience.
Frequencies are defined as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data)
In the following table, adverse reactions are listed by system organ class and MedDRA-preferred term. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Uncommon: Fungal infection including Candida infection, Pathogen resistance
Uncommon: Leukopenia, Eosinophilia
Rare: Thrombocytopenia, Neutropenia
Not known: Pancytopenia, Agranulocytosis, Haemolytic anaemia
Rare: Angioedema, Hypersensitivity (see section 4.4)
Not known: Anaphylactic shocka, Anaphylactoid shocka, (see section 4.4)
Uncommon: Anorexia
Rare: Hypoglycaemia particularly in diabetic patients (see section 4.4)
Not known: Hyperglycaemia, Hypoglycaemic coma (see section 4.4)
Common: Insomnia
Uncommon: Anxiety, Confusional state, Nervousness
Rare: Psychotic reactions (with e.g. hallucination, paranoia), Depression, Agitation, Abnormal dreams, Nightmares
Not known: Psychotic disorders with self-endangering behaviour including suicidal ideation or suicide attempt (see section 4.4)
Common: Headache, Dizziness
Uncommon: Somnolence, Tremor, Dysgeusia
Rare: Convulsion (see sections 4.3 and 4.4), Paraesthesia
Not known: Peripheral sensory neuropathy (see section 4.4), Peripheral sensory motor neuropathy (see section 4.4), Parosmia including anosmia, Dyskinesia, Extrapyramidal disorder, Ageusia, Syncope, Benign intracranial hypertension
Rare: Visual disturbances such as blurred vision (see section 4.4)
Not known: Transient vision loss (see section 4.4)
Uncommon: Vertigo
Rare: Tinnitus
Not known: Hearing loss, Hearing impaired
Rare: Tachycardia, Palpitation
Not known: Ventricular tachycardia, which may result in cardiac arrest, Ventricular arrhythmia and torsade de pointes (reported predominantly in patients with risk factors of QT prolongation), Electrocardiogram QT prolonged (see sections 4.4 and 4.9)
Common: Phlebitis
Rare: Hypotension
Uncommon: Dyspnoea
Not known: Bronchospasm, Pneumonitis allergic
Common: Diarrhoea, Vomiting, Nausea
Uncommon: Abdominal pain, Dyspepsia, Flatulence, Constipation
Not known: Diarrhoea–haemorrhagic which in very rare cases may be indicative of enterocolitis, including pseudomembranous colitis (see section 4.4), Pancreatitis
Common: Hepatic enzyme increased (ALT/AST, alkaline phosphatase, GGT)
Uncommon: Blood bilirubin increased
Not known: Jaundice and severe liver injury, including fatal cases with acute liver failure, primarily in patients with severe underlying diseases (see section 4.4), Hepatitis
Uncommon: Rash, Pruritus, Urticaria, Hyperhidrosis
Not known: Toxic epidermal necrolysis, Stevens-Johnson syndrome, Erythema multiforme, Photosensitivity reaction (see section 4.4), Leukocytoclastic vasculitis, Stomatitis
Uncommon: Arthralgia, Myalgia
Rare: Tendon disorder (see sections 4.3 and 4.4) including tendinitis (e.g. Achilles tendon), Muscular weakness which may be of special importance in patients with myasthenia gravis (see section 4.4)
Not known: Rhabdomyolysis, Tendon rupture (e.g. Achilles tendon) (see sections 4.3 and 4.4), Ligament rupture, Muscle rupture, Arthritis
Uncommon: Blood creatinine increased
Rare: Renal failure acute (e.g. due to interstitial nephritis)
Common: Infusion site reaction (pain, reddening)
Uncommon: Asthenia
Rare: Pyrexia
Not known: Pain (including pain in back, chest, and extremities)
Not known: Syndrome of inappropriate secretion of antidiuretic hormone (SIADH)
a Anaphylactic and anaphylactoid reactions may sometimes occur even after the first dose.
b Mucocutaneous reactions may sometimes occur even after the first dose
Other undesirable effects which have been associated with fluoroquinolone administration include:
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
This medicinal product must not be mixed with heparin or alkaline solutions (e.g. sodium bicarbonate). This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
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